This Program Project Grant application involves a group of investigators from Wake Forest University to understand the mechanism of action for n-3 FA, particularly those found in fish oil supplements, as relate to prostate cancer. We attempt to address the following questions: How efficient is n-3 fatty acids in reducing prostate cancer incidence, progression and metastasis in a genetically defined, immune-competent animal model with orthotopic prostate cancer? Will n-3 fatty acid intake at early age, later age or life-long have different effects on prostate cancer progression? Do inhibitors of n-6 fatty acid metabolizing enzymes have similar beneficial effect for prostate cancers as fish oil? Last but not least, what is (are) the molecular mechanism(s) by which fish oil suppress prostate cancer progression? We propose a set of four integrated and complementary research projects and three cores. They are designed to tackle a complex problem from various angles, and results from each project will help to refine others. We take advantage of our strengths of in vivo and in vitro model systems. For the first time, molecular changes (mRNA and lipid) associated with fish oil diet in the prostate will be comprehensively and systematically analyzed. In addition, conventional pathway dissection approach (phosphoinositide pathway in Project I, ecosanoid pathway in Project II, platelet activating factor pathway in Project III and syndecan pathway in Project IV) will also be applied to study the mechanism of action of fish oil on prostate cancer.